Serotonin (5-hydroxytryptamine; 5-HT) is essential for a number of central nervous system processes including the modulation of mood, perception and anxiety, the regulation of feeding behavior and the control of sleep and wakefulness. To mediate this large number of processes, multiple (>14) 5-HT receptors divided into 7 main families have evolved. This grant focuses on the 5-HT2-family of receptors, which is involved in regulating perception, appetite, anxiety, mood and cardiac development. These studies are of clinical significance because activation of 5-HT2A receptors is responsible for the actions of hallucinogens (e.g. LSD, psilocybin, mescaline) while 5-HT2B activation is involved in the cardiac side-effects of fenfluramine and related compounds (e.g. Redux, Phen/Fen) and 5-HT2C activation is important for the anorectic actions of fenfluramine. By contrast, many atypical antipsychotic and antidepressant drugs are high affinity antagonists for 5-HT2A and 5-HT2C receptors Understanding the molecular and atomic mechanisms responsible for these unique actions could lead to novel pharamacotherapies for a number of diseases including schizophrenia, depression, anxiety and feeding disorders (anorexia, bulimia) and cardiac valvulopathies. In the first specific aim, we will clarify the atomic and molecular mechanisms responsible for subtype-selective activation of 5-HT2-family receptors. The second and third specific aims will determine the relevance of conserved features of 5-HT2-family receptors for receptor-G protein activation. The fourth specific aim will determine the molecular features responsible for 5-HT2A/Gq interactions while the fifth specific aim will uncover the molecular features of Gq responsible for interacting with the 5-HT2A receptors. Novel techniques of protein biochemistry (hydroxyl-mediated 1H/2H exchange), cell biology (yeast 2-hybrid screening) and spectroscopy (FRET/BRET) will be used to arrive at testable models for 5-HT2A-Gq interactions.